N-(3-(4-(3-(diisobutylamino)propyl)piperazin-1-yl)propyl)-1H-benzo[d]imidazol-2-amine which has the structure of Formula I
belongs to a family of 1,4-bis(3-aminopropyl)piperazine derivatives previously disclosed in WO2006/051489 and which are useful for the treatment and/or prevention of neurodegenerative diseases.
The free base form of this compound presents long term stability issues likely due to oxidations occurring at the piperazine ring. In addition, the free base form does not crystallize. In terms of pharmaceutical development, crystalline forms of active ingredients are indeed preferred. They generally overcome stability issues and open up to crystallization and/or recrystallization processes which are suitable for industrial scale purification, high batch to batch reproducibility, in particular with regards to crystallinity.
Although it is known that the salification of a pharmaceutically active molecule (PAM) may improve its physico-chemical properties, the selection of a suitable salt remains a complex process. Indeed, improving physico-chemical properties goes way beyond obtaining stable solid materials. These solids must comprise a crystallized phase which has a good crystallinity and a defined morphology. In other aspects, salt forms may provide other benefits such as improving water solubility but can also be equally detrimental due to hygroscopicity, stability issues or intreseque toxicity. Hence, salt selection cannot be made arbitrarily and warrants in depth studies in the first place.
The oxalate salt of N-(3-(4-(3-(diisobutylamino)propyl)piperazin-1-yl)propyl)-1H-benzo[d]imidazol-2-amine, which by the way was reported in WO2006/051489, partly overcomes the above-mentioned drawbacks encountered with the free base. However, 4 equivalents of oxalic acid are necessary to obtain the oxalate salt as a stable powder. Consequently, the percentage by weight of pharmaceutically active molecule with oxalate salts drops to as low as 54%. The amount of drug to be administered for a given dose of PAM is thus significantly increased.
Furthermore, oxalates are not considered as one of the most pharmaceutically acceptable salt anymore. Oxalate salts are in certain cases nephrotoxic, for instance naftidofuryl oxalate is known to cause calcium oxalate crystalluria and thus kidney stones in elderly patients. In addition, due to the low solubility of calcium oxalate, increased concentration of calcium oxalate in body fluids, including urine (hyperoxaluria), can lead to the deposition of calcium oxalate (oxalosis) in the kidney tissue (nephrocalcinosis) or urinary tract (urolithiasis). Oxalosis can involve many different organs when kidneys fail to clear calcium oxalate. Deposits in blood vessels can cause painful skin ulcers that do not heal, deposits in bone marrow cause anaemia and deposits in the heart cause abnormalities of heart rhythm or poor heart function. Patients suffering from neurodegenerative diseases are generally old and suffer from other pathologies for which they receive other medications. Their kidneys are thus already highly solicited for the excretion of the drugs taken by these patients who by the way are less aware of thirst sensations and thus prone to dehydration. Excess calcium oxalate is eventually excreted in patients who have healthy kidneys and who drink a lot of water. Excess calcium oxalate is indeed a real issue in therapy, especially for the elderly. In addition, treatments of neurodegenerative diseases are often chronic, over very long periods of time, if not over lifetime. Applicant considered that due to their potential kidney and urinary tract toxicity, oxalate salts would add an undue burden to patients already weakened by their condition. Applicant thus considered oxalate salts as pharmaceutically unacceptable, especially since N-(3-(4-(3-(diisobutylamino)propyl)piperazin-1-yl)propyl)-1H-benzo[d]imidazol-2-amine requires 4 equivalents of the salt counter-ion to remain stable. Therefore, even though oxalate salts allow obtaining stable solid materials, they imply risking toxic side effects.
There is thus still a need in the art for stable, crystalline and non hygroscopic salts of N-(3-(4-(3-(diisobutylamino)propyl)piperazin-1-yl)propyl)-1H-benzo[d]imidazol-2-amine that do not present the above-mentioned drawbacks in terms of salt formation and toxicity.